bims-proteo Biomed News
on Proteostasis
Issue of 2024–05–05
29 papers selected by
Eric Chevet, INSERM
  1. HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein LMAN2L.
  2. p37 regulates VCP/p97 shuttling and functions in the nucleus and cytosol.
  3. COPII cage assembly factor Sec13 integrates information flow regulating endomembrane function in response to human variation.
  4. Turnover of EDEM1, an ERAD-enhancing factor, is mediated by multiple degradation routes.
  5. Targeted protein degradation: from mechanisms to clinic.
  6. Protein degrons and degradation: Exploring substrate recognition and pathway selection in plants.
  7. Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.
  8. Protein Condensates in the Secretory Pathway: Deciphering Biophysical Interactions and Functional Significance.
  9. ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection.
  10. Proteolytic stability and aggregation in a key metabolic enzyme of bacteria.
  11. eIF4G as a switch for heat shock mRNA translation.
  12. Molecular glues for protein-protein interactions: Progressing toward a new dream.
  13. N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation.
  14. A general approach for selection of epitope-directed binders to proteins.
  15. PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.
  16. Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas.
  17. Accelerating PROTACs Discovery Through a Direct-to-Biology Platform Enabled by Modular Photoclick Chemistry.
  18. Lysosomal dysfunction by inactivation of V-ATPase drives innate immune response in C. elegans.
  19. TRIM21-mediated ubiquitylation of TAT suppresses liver metastasis in gallbladder cancer.
  20. Non-esterified fatty acid palmitate facilitates oxidative endoplasmic reticulum stress and apoptosis of β-cells by upregulating ERO-1α expression.
  21. Species-wide quantitative transcriptomes and proteomes reveal distinct genetic control of gene expression variation in yeast.
  22. Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.
  23. Systematic analysis of proteome turnover in an organoid model of pancreatic cancer by dSILO.
  24. Systematic identification of structure-specific protein-protein interactions.
  25. Valosin-containing protein acts as a target and mediator of S-nitrosylation in the heart through distinct mechanisms.
  26. Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents.
  27. Tailored UPRE2 variants for dynamic gene regulation in yeast.
  28. Engineering tRNAs for the Ribosomal Translation of Non-proteinogenic Monomers.
  29. Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner.
  1. J Gen Virol. 2024 Apr;105(4):
    HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein LMAN2L.
    Leah M Hunter, Joanne Kite, Alice Fletcher-Etherington, Katie Nightingale, Luis Nobre, Robin Antrobus, Ceri A Fielding, Richard J Stanton, Michael P Weekes.
      The human cytomegalovirus (HCMV) pUS2 glycoprotein exploits the host's endoplasmic reticulum (ER)-associated degradation (ERAD) pathway to degrade major histocompatibility complex class I (MHC-I) and prevent antigen presentation. Beyond MHC-I, pUS2 has been shown to target a range of cellular proteins for degradation, preventing their cell surface expression. Here we have identified a novel pUS2 target, ER-resident protein lectin mannose binding 2 like (LMAN2L). pUS2 expression was both necessary and sufficient for the downregulation of LMAN2L, which was dependent on the cellular E3 ligase TRC8. Given the hypothesized role of LMAN2L in the trafficking of glycoproteins, we employed proteomic plasma membrane profiling to measure LMAN2L-dependent changes at the cell surface. A known pUS2 target, integrin alpha-6 (ITGA6), was downregulated from the surface of LMAN2L-deficient cells, but not other integrins. Overall, these results suggest a novel strategy of pUS2-mediated protein degradation whereby pUS2 targets LMAN2L to impair trafficking of ITGA6. Given that pUS2 can directly target other integrins, we propose that this single viral protein may exhibit both direct and indirect mechanisms to downregulate key cell surface molecules.
    Keywords:  cytomegalovirus; plasma membrane; protein degradation; protein trafficking; proteomics
    DOI:  https://doi.org/10.1099/jgv.0.001980
  2. Sci Adv. 2024 May 03. 10(18): eadl6082
    p37 regulates VCP/p97 shuttling and functions in the nucleus and cytosol.
    Lidia Wrobel, Johanna L Hoffmann, Xinyi Li, David C Rubinsztein.
      The AAA+-ATPase valosin-containing protein (VCP; also called p97 or Cdc48), a major protein unfolding machinery with a variety of essential functions, localizes to different subcellular compartments where it has different functions. However, the processes regulating the distribution of VCP between the cytosol and nucleus are not understood. Here, we identified p37 (also called UBXN2B) as a major factor regulating VCP nucleocytoplasmic shuttling. p37-dependent VCP localization was crucial for local cytosolic VCP functions, such as autophagy, and nuclear functions in DNA damage repair. Mutations in VCP causing multisystem proteinopathy enhanced its association with p37, leading to decreased nuclear localization of VCP, which enhanced susceptibility to DNA damage accumulation. Both VCP localization and DNA damage susceptibility in cells with such mutations were normalized by lowering p37 levels. Thus, we uncovered a mechanism by which VCP nucleocytoplasmic distribution is fine-tuned, providing a means for VCP to respond appropriately to local needs.
    DOI:  https://doi.org/10.1126/sciadv.adl6082
  3. Sci Rep. 2024 May 03. 14(1): 10160
    COPII cage assembly factor Sec13 integrates information flow regulating endomembrane function in response to human variation.
    Frédéric Anglès, Vijay Gupta, Chao Wang, William E Balch.
      How information flow is coordinated for managing transit of 1/3 of the genome through endomembrane pathways by the coat complex II (COPII) system in response to human variation remains an enigma. By examining the interactome of the COPII cage-assembly component Sec13, we show that it is simultaneously associated with multiple protein complexes that facilitate different features of a continuous program of chromatin organization, transcription, translation, trafficking, and degradation steps that are differentially sensitive to Sec13 levels. For the trafficking step, and unlike other COPII components, reduction of Sec13 expression decreased the ubiquitination and degradation of wild-type (WT) and F508del variant cargo protein cystic fibrosis transmembrane conductance regulator (CFTR) leading to a striking increase in fold stability suggesting that the events differentiating export from degradation are critically dependent on COPII cage assembly at the ER Golgi intermediate compartment (ERGIC) associated recycling and degradation step linked to COPI exchange. Given Sec13's multiple roles in protein complex assemblies that change in response to its expression, we suggest that Sec13 serves as an unanticipated master regulator coordinating information flow from the genome to the proteome to facilitate spatial covariant features initiating and maintaining design and function of membrane architecture in response to human variation.
    DOI:  https://doi.org/10.1038/s41598-024-60687-2
  4. Genes Cells. 2024 Apr 29.
    Turnover of EDEM1, an ERAD-enhancing factor, is mediated by multiple degradation routes.
    Riko Katsuki, Mai Kanuka, Ren Ohta, Shusei Yoshida, Taku Tamura.
      Quality-based protein production and degradation in the endoplasmic reticulum (ER) are essential for eukaryotic cell survival. During protein maturation in the ER, misfolded or unassembled proteins are destined for disposal through a process known as ER-associated degradation (ERAD). EDEM1 is an ERAD-accelerating factor whose gene expression is upregulated by the accumulation of aberrant proteins in the ER, known as ER stress. Although the role of EDEM1 in ERAD has been studied in detail, the turnover of EDEM1 by intracellular degradation machinery, including the proteasome and autophagy, is not well understood. To clarify EDEM1 regulation in the protein level, degradation mechanism of EDEM1 was examined. Our results indicate that both ERAD and autophagy degrade EDEM1 alike misfolded degradation substrates, although each degradation machinery targets EDEM1 in different folded states of proteins. We also found that ERAD factors, including the SEL1L/Hrd1 complex, YOD1, XTP3B, ERdj3, VIMP, BAG6, and JB12, but not OS9, are involved in EDEM1 degradation in a mannose-trimming-dependent and -independent manner. Our results suggest that the ERAD accelerating factor, EDEM1, is turned over by the ERAD itself, similar to ERAD clients.
    Keywords:  EDEM1; ER quality control; ER stress; ERAD; autophagy; proteasome; protein degradation; protein turnover; unfolded protein response
    DOI:  https://doi.org/10.1111/gtc.13117
  5. Nat Rev Mol Cell Biol. 2024 Apr 29.
    Targeted protein degradation: from mechanisms to clinic.
    Jonathan M Tsai, Radosław P Nowak, Benjamin L Ebert, Eric S Fischer.
      Targeted protein degradation refers to the use of small molecules to induce the selective degradation of proteins. In its most common form, this degradation is achieved through ligand-mediated neo-interactions between ubiquitin E3 ligases - the principal waste disposal machines of a cell - and the protein targets of interest, resulting in ubiquitylation and subsequent proteasomal degradation. Notable advances have been made in biological and mechanistic understanding of serendipitously discovered degraders. This improved understanding and novel chemistry has not only provided clinical proof of concept for targeted protein degradation but has also led to rapid growth of the field, with dozens of investigational drugs in active clinical trials. Two distinct classes of protein degradation therapeutics are being widely explored: bifunctional PROTACs and molecular glue degraders, both of which have their unique advantages and challenges. Here, we review the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. We also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take.
    DOI:  https://doi.org/10.1038/s41580-024-00729-9
  6. Plant Cell. 2024 May 03. pii: koae141. [Epub ahead of print]
    Protein degrons and degradation: Exploring substrate recognition and pathway selection in plants.
    Erika Isono, Jianming Li, Pablo Pulido, Wei Siao, Steven H Spoel, Zhishuo Wang, Xiaohong Zhuang, Marco Trujillo.
      Proteome composition is dynamic and influenced by many internal and external cues, including developmental signals, light availability, or environmental stresses. Protein degradation, in synergy with protein biosynthesis, allows cells to respond to various stimuli and adapt by reshaping the proteome. Protein degradation mediates the final and irreversible disassembly of proteins, which is important for protein quality control and to eliminate misfolded or damaged proteins, as well as entire organelles. Consequently, it contributes to cell resilience by buffering against protein or organellar damage caused by stresses. Moreover, protein degradation plays important roles in cell signaling, as well as transcriptional and translational events. The intricate task of recognizing specific proteins for degradation is achieved by specialized systems that are tailored to the substrate's physicochemical properties and subcellular localization. These systems recognize diverse substrate cues collectively referred to as "degrons", which can assume a range of structural configurations. They are molecular surfaces recognized by E3 ligases of the ubiquitin-proteasome system, but can also be considered as general features recognized by other degradation systems, including autophagy or even organellar proteases. Here we provide an overview of the newest developments in the field, delving into the intricate processes of protein recognition and elucidating the pathways through which they are recruited for degradation.
    DOI:  https://doi.org/10.1093/plcell/koae141
  7. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2322164121
    Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.
    Vi T Tang, Jie Xiang, Zhimin Chen, Joseph McCormick, Prabhodh S Abbineni, Xiao-Wei Chen, Mark Hoenerhoff, Brian T Emmer, Rami Khoriaty, Jiandie D Lin, David Ginsburg.
      Proteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode two SAR1 paralogs, SAR1A and SAR1B. While these paralogs exhibit ~90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation of Sar1a in mice results in lethality during midembryogenesis. We also confirm previous reports that complete deficiency of murine Sar1b results in perinatal lethality. In contrast, we demonstrate that deletion of Sar1b restricted to hepatocytes is compatible with survival, though resulting in hypocholesterolemia that can be rescued by adenovirus-mediated overexpression of either SAR1A or SAR1B. To further examine the in vivo function of these two paralogs, we genetically engineered mice with the Sar1a coding sequence replacing that of Sar1b at the endogenous Sar1b locus. Mice homozygous for this allele survive to adulthood and are phenotypically normal, demonstrating complete or near-complete overlap in function between the two SAR1 protein paralogs in mice. These data also suggest upregulation of SAR1A gene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.
    Keywords:  COPII; SAR1; endoplasmic reticulum
    DOI:  https://doi.org/10.1073/pnas.2322164121
  8. Biophys J. 2024 May 02. pii: S0006-3495(24)00311-4. [Epub ahead of print]
    Protein Condensates in the Secretory Pathway: Deciphering Biophysical Interactions and Functional Significance.
    Felix Campelo, Javier Vera Lillo, Julia von Blume.
      The emergence of phase separation phenomena among macromolecules has identified biomolecular condensates as fundamental cellular organizers. These condensates concentrate specific components and accelerate biochemical reactions without relying on membrane boundaries. While extensive studies have revealed a large variety of nuclear and cytosolic membraneless organelles, we are witnessing a surge in the exploration of protein condensates associated with the membranes of the secretory pathway, such as the endoplasmic reticulum (ER) and the Golgi apparatus. This Review focuses on protein condensates in the secretory pathway and discusses their impact on the organization and functions of this cellular process. Moreover, we explore the modes of condensate-membrane association and the biophysical and cellular consequences of protein condensate interactions with secretory pathway membranes.
    DOI:  https://doi.org/10.1016/j.bpj.2024.04.031
  9. Cell Rep. 2024 Apr 29. pii: S2211-1247(24)00484-4. [Epub ahead of print]43(5): 114156
    ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection.
    Luis O Correa-Medero, Shayna E Jankowski, Hanna S Hong, Nicholas D Armas, Aditi I Vijendra, Mack B Reynolds, Garrett M Fogo, Dominik Awad, Alexander T Dils, Kantaro A Inoki, Reid G Williams, Annabelle M Ye, Nadezhda Svezhova, Francisco Gomez-Rivera, Kathleen L Collins, Mary X O'Riordan, Thomas H Sanderson, Costas A Lyssiotis, Shannon A Carty.
      The maintenance of antigen-specific CD8+ T cells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8+ T cell loss are not completely understood. Uncovering the pathways underlying the limited persistence of CD8+ T cells would be of significant benefit for developing novel strategies of promoting T cell persistence. Here, we demonstrate that murine CD8+ T cells experience endoplasmic reticulum (ER) stress following activation and that the ER-associated degradation (ERAD) adapter Sel1L is induced in activated CD8+ T cells. Sel1L loss limits CD8+ T cell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal bioenergetics and c-Myc expression. Finally, we demonstrate that human CD8+ T cells experience ER stress upon activation and that ER stress is negatively associated with improved T cell functionality in T cell-redirecting therapies. Together, these results demonstrate that ER stress and ERAD are important regulators of T cell function and persistence.
    Keywords:  CD8 T cell; CP: Immunology; ER stress; ERAD; Myc; T cell memory; immunometabolism; protein homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114156
  10. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2301458121
    Proteolytic stability and aggregation in a key metabolic enzyme of bacteria.
    Dan Pollack, Takashi Nozoe, Edo Kussell.
      Proteins that are kinetically stable are thought to be less prone to both aggregation and proteolysis. We demonstrate that the classical lac system of Escherichia coli can be leveraged as a model system to study this relation. β-galactosidase (LacZ) plays a critical role in lactose metabolism and is an extremely stable protein that can persist in growing cells for multiple generations after expression has stopped. By attaching degradation tags to the LacZ protein, we find that LacZ can be transiently degraded during lac operon expression but once expression has stopped functional LacZ is protected from degradation. We reversibly destabilize its tetrameric assembly using α-complementation, and show that unassembled LacZ monomers and dimers can either be degraded or lead to formation of aggregates within cells, while the tetrameric state protects against proteolysis and aggregation. We show that the presence of aggregates is associated with cell death, and that these proteotoxic stress phenotypes can be alleviated by attaching an ssrA tag to LacZ monomers which leads to their degradation. We unify our findings using a biophysical model that enables the interplay of protein assembly, degradation, and aggregation to be studied quantitatively in vivo. This work may yield approaches to reversing and preventing protein-misfolding disease states, while elucidating the functions of proteolytic stability in constant and fluctuating environments.
    Keywords:  lac operon; protein aggregation; protein degradation; ssrA; β-galactosidase
    DOI:  https://doi.org/10.1073/pnas.2301458121
  11. Mol Cell. 2024 May 02. pii: S1097-2765(24)00280-6. [Epub ahead of print]84(9): 1633-1634
    eIF4G as a switch for heat shock mRNA translation.
    Yi Liu, Peiguo Yang.
      The heat shock response is crucial for cell survival. In this issue of Molecular Cell, Desroches Altamirano et al.1 demonstrate that a temperature-induced conformational change in the translation initiation factor eIF4G is a key mechanism regulating translation during the heat shock response.
    DOI:  https://doi.org/10.1016/j.molcel.2024.04.002
  12. Cell Chem Biol. 2024 Apr 25. pii: S2451-9456(24)00130-2. [Epub ahead of print]
    Molecular glues for protein-protein interactions: Progressing toward a new dream.
    Markella Konstantinidou, Michelle R Arkin.
      The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances over the past decade (2014-2023) focusing on molecular glues (MGs)-monovalent small molecules that induce proximity, either by stabilizing native interactions or by inducing neomorphic interactions. We include both serendipitous and rational discoveries and describe the different approaches that were used to identify them. We classify the compounds in three main categories: degradative MGs, non-degradative MGs or PPI stabilizers, and MGs that induce self-association. Diverse, illustrative examples with structural data are described in detail, emphasizing the elements of molecular recognition and cooperative binding at the interface that are fundamental for a MG mechanism of action.
    Keywords:  PPI; cooperativity; covalent; degraders; molecular glues; molecular recognition; native interactions; neomorphic; proximity; stabilizers; ternary complex
    DOI:  https://doi.org/10.1016/j.chembiol.2024.04.002
  13. Immunity. 2024 Apr 26. pii: S1074-7613(24)00209-7. [Epub ahead of print]
    N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation.
    Alexander D Gitlin, Allie Maltzman, Yuzuka Kanno, Klaus Heger, Rohit Reja, Alexander F Schubert, Linsey J Wierciszewski, Homer Pantua, Sharookh B Kapadia, Seth F Harris, Joshua D Webster, Kim Newton, Vishva M Dixit.
      The ubiquitin-binding endoribonuclease N4BP1 potently suppresses cytokine production by Toll-like receptors (TLRs) that signal through the adaptor MyD88 but is inactivated via caspase-8-mediated cleavage downstream of death receptors, TLR3, or TLR4. Here, we examined the mechanism whereby N4BP1 limits inflammatory responses. In macrophages, deletion of N4BP1 prolonged activation of inflammatory gene transcription at late time points after TRIF-independent TLR activation. Optimal suppression of inflammatory cytokines by N4BP1 depended on its ability to bind polyubiquitin chains, as macrophages and mice-bearing inactivating mutations in a ubiquitin-binding motif in N4BP1 displayed increased TLR-induced cytokine production. Deletion of the noncanonical IκB kinases (ncIKKs), Tbk1 and Ikke, or their adaptor Tank phenocopied N4bp1 deficiency and enhanced macrophage responses to TLR1/2, TLR7, or TLR9 stimulation. Mechanistically, N4BP1 acted in concert with the ncIKKs to limit the duration of canonical IκB kinase (IKKα/β) signaling. Thus, N4BP1 and the ncIKKs serve as an important checkpoint against over-exuberant innate immune responses.
    Keywords:  Toll-like receptors; cytokines; inflammation; innate immunity; signal transduction
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.004
  14. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2317307121
    A general approach for selection of epitope-directed binders to proteins.
    Jie Zhou, Chau Q Le, Yun Zhang, James A Wells.
      Directing antibodies to a particular epitope among many possible on a target protein is a significant challenge. Here, we present a simple and general method for epitope-directed selection (EDS) using a differential phage selection strategy. This involves engineering the protein of interest (POI) with the epitope of interest (EOI) mutated using a systematic bioinformatics algorithm to guide the local design of an EOI decoy variant. Using several alternating rounds of negative selection with the EOI decoy variant followed by positive selection on the wild-type POI, we were able to identify highly specific and potent antibodies to five different EOI antigens that bind and functionally block known sites of proteolysis. Among these, we developed highly specific antibodies that target the proteolytic site on the CUB domain containing protein 1 (CDCP1) to prevent its proteolysis allowing us to study the cellular maturation of this event that triggers malignancy. We generated antibodies that recognize the junction between the pro- and catalytic domains for three different matrix metalloproteases (MMPs), MMP1, MMP3, and MMP9, that selectively block activation of each of these enzymes and impair cell migration. We targeted a proteolytic epitope on the cell surface receptor, EPH Receptor A2 (EphA2), that is known to transform it from a tumor suppressor to an oncoprotein. We believe that the EDS method greatly facilitates the generation of antibodies to specific EOIs on a wide range of proteins and enzymes for broad therapeutic and diagnostic applications.
    Keywords:  cancer therapy; differential selection; epitope-directed antibody; phage display; proteolysis
    DOI:  https://doi.org/10.1073/pnas.2317307121
  15. NPJ Parkinsons Dis. 2024 Apr 29. 10(1): 93
    PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.
    Roberta Filograna, Jule Gerlach, Hae-Na Choi, Giovanni Rigoni, Michela Barbaro, Mikael Oscarson, Seungmin Lee, Katarina Tiklova, Markus Ringnér, Camilla Koolmeister, Rolf Wibom, Sara Riggare, Inger Nennesmo, Thomas Perlmann, Anna Wredenberg, Anna Wedell, Elisa Motori, Per Svenningsson, Nils-Göran Larsson.
      Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson's disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.
    DOI:  https://doi.org/10.1038/s41531-024-00707-0
  16. Cancer Cell. 2024 Apr 25. pii: S1535-6108(24)00131-4. [Epub ahead of print]
    Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas.
    Jaewoo Choi, Michele Ceribelli, James D Phelan, Björn Häupl, Da Wei Huang, George W Wright, Tony Hsiao, Vivian Morris, Francesco Ciccarese, Boya Wang, Sean Corcoran, Sebastian Scheich, Xin Yu, Weihong Xu, Yandan Yang, Hong Zhao, Joyce Zhou, Grace Zhang, Jagan Muppidi, Giorgio G Inghirami, Thomas Oellerich, Wyndham H Wilson, Craig J Thomas, Louis M Staudt.
      Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.
    Keywords:  ABC; B cell receptor; CSK; DLBCL; GCB; PI3 kinase; combination therapy; dexamethasone; glucocorticoids; prednisone
    DOI:  https://doi.org/10.1016/j.ccell.2024.04.007
  17. Adv Sci (Weinh). 2024 Apr 30. e2400594
    Accelerating PROTACs Discovery Through a Direct-to-Biology Platform Enabled by Modular Photoclick Chemistry.
    Ke-Nian Yan, Yong-Qiang Nie, Jia-Yu Wang, Guang-Liang Yin, Qia Liu, Hao Hu, Xiaoxia Sun, Xiao-Hua Chen.
      Proteolysis targeting chimeras (PROTACs) have emerged as a promising strategy for drug discovery and exploring protein functions, offering a revolutionary therapeutic modality. Currently, the predominant approach to PROTACs discovery mainly relies on an empirical design-synthesis-evaluation process involving numerous cycles of labor-intensive synthesis-purification and bioassay data collection. Therefore, the development of innovative methods to expedite PROTAC synthesis and exploration of chemical space remains highly desired. Here, a direct-to-biology strategy is reported to streamline the synthesis of PROTAC libraries on plates, enabling the seamless transfer of reaction products to cell-based bioassays without the need for additional purification. By integrating amide coupling and light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) photoclick chemistry into a plate-based synthetic process, this strategy produces PROTAC libraries with high efficiency and structural diversity. Moreover, by employing this platform for PROTACs screening, we smoothly found potent PROTACs effectively inhibit triple-negative breast cancer (TNBC) cell growth and induce rapid, selective targeted degradation of cyclin-dependent kinase 9 (CDK9). The study introduces a versatile platform for assembling PROTACs on plates, followed by direct biological evaluation. This approach provides a promising opportunity for high-throughput synthesis of PROTAC libraries, thereby enhancing the efficiency of exploring chemical space and accelerating the discovery of PROTACs.
    Keywords:  High‐throughput chemical synthesis; PROTACs library; modular synthesis; photoclick chemistry; targeted protein degradation
    DOI:  https://doi.org/10.1002/advs.202400594
  18. Cell Rep. 2024 Apr 26. pii: S2211-1247(24)00466-2. [Epub ahead of print]43(5): 114138
    Lysosomal dysfunction by inactivation of V-ATPase drives innate immune response in C. elegans.
    Xuepiao Pu, Bin Qi.
      Pathogens target vacuolar ATPase (V-ATPase) to inhibit lysosomal acidification or lysosomal fusion, causing lysosomal dysfunction. However, it remains unknown whether cells can detect dysfunctional lysosomes and initiate an immune response. In this study, we discover that dysfunction of lysosomes caused by inactivation of V-ATPase enhances innate immunity against bacterial infections. We find that lysosomal V-ATPase interacts with DVE-1, whose nuclear localization serves as a proxy for the induction of mitochondrial unfolded protein response (UPRmt). The inactivation of V-ATPase promotes the nuclear localization of DVE-1, activating UPRmt and inducing downstream immune response genes. Furthermore, pathogen resistance conferred by inactivation of V-ATPase requires dve-1 and its downstream immune effectors. Interestingly, animals grow slower after vha RNAi, suggesting that the vha-RNAi-induced immune response costs the most energy through activation of DVE-1, which trades off with growth. This study reveals how dysfunctional lysosomes can trigger an immune response, emphasizing the importance of conserving energy during immune defense.
    Keywords:  C. elegans; CP: Immunology; UPR(mt); V-ATPase; immunity; lysosomes; mitochondria; mitochondrial surveillance; pathogen
    DOI:  https://doi.org/10.1016/j.celrep.2024.114138
  19. Cancer Lett. 2024 Apr 30. pii: S0304-3835(24)00316-1. [Epub ahead of print] 216923
    TRIM21-mediated ubiquitylation of TAT suppresses liver metastasis in gallbladder cancer.
    Ziyou Wu, Jian Zhang, Ziyao Jia, Ziyi Yang, Shilei Liu, Huakai Wang, Cheng Zhao, Jingwei Zhao, Qiuyi Tang, Yichen Xiong, Yue Yang, Yu Zhang, Zhe Zhou, Juanqing Yue, Fan Xiao, Quan Sun, Albie Gong, Wenyan Yao, Huaifeng Li, Xiaoling Song, Yuanyuan Ye, Yidi Zhu, Ping Dong, Fei Ma, Xiangsong Wu, Wei Gong.
      Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.
    Keywords:  Gallbladder cancer; Liver metastasis; Mitophagy; TAT; TRIM21
    DOI:  https://doi.org/10.1016/j.canlet.2024.216923
  20. Redox Biol. 2024 Apr 27. pii: S2213-2317(24)00146-0. [Epub ahead of print]73 103170
    Non-esterified fatty acid palmitate facilitates oxidative endoplasmic reticulum stress and apoptosis of β-cells by upregulating ERO-1α expression.
    Sarah Sharifi, Tomoko Yamamoto, Andre Zeug, Matthias Elsner, Edward Avezov, Ilir Mehmeti.
      Adipose tissue-derived non-esterified saturated long-chain fatty acid palmitate (PA) decisively contributes to β-cell demise in type 2 diabetes mellitus in part through the excessive generation of hydrogen peroxide (H2O2). The endoplasmic reticulum (ER) as the primary site of oxidative protein folding could represent a significant source of H2O2. Both ER-oxidoreductin-1 (ERO-1) isoenzymes, ERO-1α and ERO-1β, catalyse oxidative protein folding within the ER, generating equimolar amounts of H2O2 for every disulphide bond formed. However, whether ERO-1-derived H2O2 constitutes a potential source of cytotoxic luminal H2O2 under lipotoxic conditions is still unknown. Here, we demonstrate that both ERO-1 isoforms are expressed in pancreatic β-cells, but interestingly, PA only significantly induces ERO-1α. Its specific deletion significantly attenuates PA-mediated oxidative ER stress and subsequent β-cell death by decreasing PA-mediated ER-luminal and mitochondrial H2O2 accumulation, by counteracting the dysregulation of ER Ca2+ homeostasis, and by mitigating the reduction of mitochondrial membrane potential and lowered ATP content. Moreover, ablation of ERO-1α alleviated PA-induced hyperoxidation of the ER redox milieu. Importantly, ablation of ERO-1α did not affect the insulin secretory capacity, the unfolded protein response, or ER redox homeostasis under steady-state conditions. The involvement of ERO-1α-derived H2O2 in PA-mediated β-cell lipotoxicity was corroborated by the overexpression of a redox-active ERO-1α underscoring the proapoptotic activity of ERO-1α in pancreatic β-cells. Overall, our findings highlight the critical role of ERO-1α-derived H2O2 in lipotoxic ER stress and β-cell failure.
    Keywords:  ER oxidoreductin-1α; Hydrogen peroxide; Lipotoxicity; Palmitate; Type 2 diabetes; β-cell death
    DOI:  https://doi.org/10.1016/j.redox.2024.103170
  21. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2319211121
    Species-wide quantitative transcriptomes and proteomes reveal distinct genetic control of gene expression variation in yeast.
    Elie Marcel Teyssonnière, Pauline Trébulle, Julia Muenzner, Victor Loegler, Daniela Ludwig, Fatma Amari, Michael Mülleder, Anne Friedrich, Jing Hou, Markus Ralser, Joseph Schacherer.
      Gene expression varies between individuals and corresponds to a key step linking genotypes to phenotypes. However, our knowledge regarding the species-wide genetic control of protein abundance, including its dependency on transcript levels, is very limited. Here, we have determined quantitative proteomes of a large population of 942 diverse natural Saccharomyces cerevisiae yeast isolates. We found that mRNA and protein abundances are weakly correlated at the population gene level. While the protein coexpression network recapitulates major biological functions, differential expression patterns reveal proteomic signatures related to specific populations. Comprehensive genetic association analyses highlight that genetic variants associated with variation in protein (pQTL) and transcript (eQTL) levels poorly overlap (3%). Our results demonstrate that transcriptome and proteome are governed by distinct genetic bases, likely explained by protein turnover. It also highlights the importance of integrating these different levels of gene expression to better understand the genotype-phenotype relationship.
    Keywords:  gene regulation; genetic control; pQTL; quantitative proteomes; yeast
    DOI:  https://doi.org/10.1073/pnas.2319211121
  22. Cancer Discov. 2024 Apr 17. OF1-OF22
    Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.
    Jiayu Ye, John M Baer, Douglas V Faget, Vasilios A Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Xianmin Luo, Satarupa Mullick Bagchi, Jad I Belle, Edward Campos, Michael Friedman, Deborah J Veis, Erik S Knudsen, Agnieszka K Witkiewicz, Scott Powers, Gregory D Longmore, David G DeNardo, Sheila A Stewart.
      The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development.
    SIGNIFICANCE: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0426
  23. Cell Rep Methods. 2024 Apr 24. pii: S2667-2375(24)00091-2. [Epub ahead of print] 100760
    Systematic analysis of proteome turnover in an organoid model of pancreatic cancer by dSILO.
    Alison B Ross, Darvesh Gorhe, Jenny Kim Kim, Stefanie Hodapp, Lela DeVine, Karina M Chan, Iok In Christine Chio, Marko Jovanovic, Marina Ayres Pereira.
      The role of protein turnover in pancreatic ductal adenocarcinoma (PDA) metastasis has not been previously investigated. We introduce dynamic stable-isotope labeling of organoids (dSILO): a dynamic SILAC derivative that combines a pulse of isotopically labeled amino acids with isobaric tandem mass-tag (TMT) labeling to measure proteome-wide protein turnover rates in organoids. We applied it to a PDA model and discovered that metastatic organoids exhibit an accelerated global proteome turnover compared to primary tumor organoids. Globally, most turnover changes are not reflected at the level of protein abundance. Interestingly, the group of proteins that show the highest turnover increase in metastatic PDA compared to tumor is involved in mitochondrial respiration. This indicates that metastatic PDA may adopt alternative respiratory chain functionality that is controlled by the rate at which proteins are turned over. Collectively, our analysis of proteome turnover in PDA organoids offers insights into the mechanisms underlying PDA metastasis.
    Keywords:  CP: Biotechnology; CP: Cancer biology; PDA; SILAC; dSILO; metastases; protein half-life; protein turnover; respirasome
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100760
  24. Mol Syst Biol. 2024 May 03.
    Systematic identification of structure-specific protein-protein interactions.
    Aleš Holfeld, Dina Schuster, Fabian Sesterhenn, Alison K Gillingham, Patrick Stalder, Walther Haenseler, Inigo Barrio-Hernandez, Dhiman Ghosh, Jane Vowles, Sally A Cowley, Luise Nagel, Basavraj Khanppnavar, Tetiana Serdiuk, Pedro Beltrao, Volodymyr M Korkhov, Sean Munro, Roland Riek, Natalie de Souza, Paola Picotti.
      The physical interactome of a protein can be altered upon perturbation, modulating cell physiology and contributing to disease. Identifying interactome differences of normal and disease states of proteins could help understand disease mechanisms, but current methods do not pinpoint structure-specific PPIs and interaction interfaces proteome-wide. We used limited proteolysis-mass spectrometry (LiP-MS) to screen for structure-specific PPIs by probing for protease susceptibility changes of proteins in cellular extracts upon treatment with specific structural states of a protein. We first demonstrated that LiP-MS detects well-characterized PPIs, including antibody-target protein interactions and interactions with membrane proteins, and that it pinpoints interfaces, including epitopes. We then applied the approach to study conformation-specific interactors of the Parkinson's disease hallmark protein alpha-synuclein (aSyn). We identified known interactors of aSyn monomer and amyloid fibrils and provide a resource of novel putative conformation-specific aSyn interactors for validation in further studies. We also used our approach on GDP- and GTP-bound forms of two Rab GTPases, showing detection of differential candidate interactors of conformationally similar proteins. This approach is applicable to screen for structure-specific interactomes of any protein, including posttranslationally modified and unmodified, or metabolite-bound and unbound protein states.
    Keywords:  Limited Proteolysis; Mass Spectrometry; Protein–protein Interactions; Structural Proteomics; Structure-Specific Interactions
    DOI:  https://doi.org/10.1038/s44320-024-00037-6
  25. Redox Biol. 2024 Apr 26. pii: S2213-2317(24)00142-3. [Epub ahead of print]72 103166
    Valosin-containing protein acts as a target and mediator of S-nitrosylation in the heart through distinct mechanisms.
    Xiaomeng Shi, Molly O'Connor, Hongyu Qiu.
      S-nitrosylation (SNO) is an emerging paradigm of redox signaling protecting cells against oxidative stress in the heart. Our previous studies demonstrated that valosin-containing protein (VCP), an ATPase-associated protein, is a vital mediator protecting the heart against cardiac stress and ischemic injury. However, the molecular regulations conferred by VCP in the heart are not fully understood. In this study, we explored the potential role of VCP in cardiac protein SNO using multiple cardiac-specific genetically modified mouse models and various analytical techniques including biotin switch assay, liquid chromatography, mass spectrometry, and western blotting. Our results showed that cardiac-specific overexpression of VCP led to an overall increase in the levels of SNO-modified cardiac proteins in the transgenic (TG) vs. wild-type (WT) mice. Mass spectrometry analysis identified mitochondrial proteins involved in respiration, metabolism, and detoxification as primary targets of SNO modification in VCP-overexpressing mouse hearts. Particularly, we found that VCP itself underwent SNO modification at a specific cysteine residue in its N-domain. Additionally, our study demonstrated that glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis, also experienced increased SNO in response to VCP overexpression. While deletion of inducible nitric oxide synthase (iNOS) in VCP TG mice did not affect VCP SNO, it did abolish SNO modification in mitochondrial complex proteins, suggesting a dual mechanism of regulation involving both iNOS-dependent and independent pathways. Overall, our findings shed light on post-translational modification of VCP in the heart, unveiling a previously unrecognized role for VCP in regulating cardiac protein SNO and offering new insights into its function in cardiac protection.
    Keywords:  Cardiac protein; Inducible nitric oxide synthase; Mitochondria; Post-translational modification; S-nitrosylation; Valosin-containing protein
    DOI:  https://doi.org/10.1016/j.redox.2024.103166
  26. J Med Chem. 2024 May 01.
    Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents.
    Zunhua Yang, Yuqi Ying, Shaobing Cheng, Jiamin Wu, Ziwei Zhang, Pei Hu, Jian Xiong, Huilan Li, Qing Zeng, Zhifang Cai, Yulin Feng, Yuanying Fang.
      PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 μM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c00356
  27. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2315729121
    Tailored UPRE2 variants for dynamic gene regulation in yeast.
    Chufan Xiao, Xiufang Liu, Yuyang Pan, Yanling Li, Ling Qin, Zhibo Yan, Yunzi Feng, Mouming Zhao, Mingtao Huang.
      Genetic elements are foundational in synthetic biology serving as vital building blocks. They enable programming host cells for efficient production of valuable chemicals and recombinant proteins. The unfolded protein response (UPR) is a stress pathway in which the transcription factor Hac1 interacts with the upstream unfolded protein response element (UPRE) of the promoter to restore endoplasmic reticulum (ER) homeostasis. Here, we created a UPRE2 mutant (UPRE2m) library. Several rounds of screening identified many elements with enhanced responsiveness and a wider dynamic range. The most active element m84 displayed a response activity 3.72 times higher than the native UPRE2. These potent elements are versatile and compatible with various promoters. Overexpression of HAC1 enhanced stress signal transduction, expanding the signal output range of UPRE2m. Through molecular modeling and site-directed mutagenesis, we pinpointed the DNA-binding residue Lys60 in Hac1(Hac1-K60). We also confirmed that UPRE2m exhibited a higher binding affinity to Hac1. This shed light on the mechanism underlying the Hac1-UPRE2m interaction. Importantly, applying UPRE2m for target gene regulation effectively increased both recombinant protein production and natural product synthesis. These genetic elements provide valuable tools for dynamically regulating gene expression in yeast cell factories.
    Keywords:  Hac1; UPRE2 variants; responsive promoter; unfolded protein response
    DOI:  https://doi.org/10.1073/pnas.2315729121
  28. Chem Rev. 2024 Apr 30.
    Engineering tRNAs for the Ribosomal Translation of Non-proteinogenic Monomers.
    Maxwell Sigal, Satomi Matsumoto, Adam Beattie, Takayuki Katoh, Hiroaki Suga.
      Ribosome-dependent protein biosynthesis is an essential cellular process mediated by transfer RNAs (tRNAs). Generally, ribosomally synthesized proteins are limited to the 22 proteinogenic amino acids (pAAs: 20 l-α-amino acids present in the standard genetic code, selenocysteine, and pyrrolysine). However, engineering tRNAs for the ribosomal incorporation of non-proteinogenic monomers (npMs) as building blocks has led to the creation of unique polypeptides with broad applications in cellular biology, material science, spectroscopy, and pharmaceuticals. Ribosomal polymerization of these engineered polypeptides presents a variety of challenges for biochemists, as translation efficiency and fidelity is often insufficient when employing npMs. In this Review, we will focus on the methodologies for engineering tRNAs to overcome these issues and explore recent advances both in vitro and in vivo. These efforts include increasing orthogonality, recruiting essential translation factors, and creation of expanded genetic codes. After our review on the biochemical optimizations of tRNAs, we provide examples of their use in genetic code manipulation, with a focus on the in vitro discovery of bioactive macrocyclic peptides containing npMs. Finally, an analysis of the current state of tRNA engineering is presented, along with existing challenges and future perspectives for the field.
    DOI:  https://doi.org/10.1021/acs.chemrev.3c00894
  29. Cell Rep. 2024 Apr 26. pii: S2211-1247(24)00477-7. [Epub ahead of print]43(5): 114149
    Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner.
    Davy Vanhoutte, Tobias G Schips, Rachel A Minerath, Jiuzhou Huo, Naga Swathi Sree Kavuri, Vikram Prasad, Suh-Chin Lin, Michael J Bround, Michelle A Sargent, Christopher M Adams, Jeffery D Molkentin.
      Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound muscle atrophy with age-dependent decreases in exercise capacity and premature lethality. Mechanistically, Thbs1 activates transforming growth factor β (TGFβ)-Smad2/3 signaling, which also induces activating transcription factor 4 (ATF4) expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to facilitate muscle atrophy. Indeed, myofiber-specific inhibition of TGFβ-receptor signaling represses the induction of ATF4, normalizes ALP and UPS, and partially restores muscle mass in Thbs1 Tg mice. Similarly, myofiber-specific deletion of Smad2 and Smad3 or the Atf4 gene antagonizes Thbs1-induced muscle atrophy. More importantly, Thbs1-/- mice show significantly reduced levels of denervation- and caloric restriction-mediated muscle atrophy, along with blunted TGFβ-Smad3-ATF4 signaling. Thus, Thbs1-mediated TGFβ-Smad3-ATF4 signaling in skeletal muscle regulates tissue rarefaction, suggesting a target for atrophy-based muscle diseases and sarcopenia with aging.
    Keywords:  ATF4; CP: Metabolism; TGFβ; atrophy; autophagy; extracellular matrix; proteasome; skeletal muscle; thrombospondin
    DOI:  https://doi.org/10.1016/j.celrep.2024.114149
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